Sex determination is the process by which the bipotential gonad differentiates into either a testis in XY embryos or an ovary in XX embryos. This process not only initiates the sexual development of the individual but also influences adult physiology and the progression of many diseases. In 1990, the testis-determining gene was identified as SRY. More recently, our team identified the ovarian-determining factor as an alternatively spliced variant of WT1. However, the mechanism driving the production of this splice variant remains unknown. Recently, we identified a novel gene that is essential for sex determination, as its absence results in a failure of gonadal sexual differentiation. This discovery revealed a previously unrecognized regulatory layer in sex determination: post-transcriptional regulation.

Our current objective is to elucidate the mechanisms underlying this regulation and determine how it affects the expression of key genes involved in gonadal sex differentiation, including the sex determinants. Using genetic models, high-resolution microscopy, advanced transcriptomic tools, and biochemical analyses, we aim to uncover how specific candidate factors contribute to the alternative splicing of WT1, leading to the production of the ovarian determinant. We will also examine mRNA chemical modifications, structural dynamics, and stability in mutant versus control gonads. This research will deepen our understanding of the regulatory mechanisms governing sex determination and may pave the way for new diagnostic tools for the more than 40% of individuals with unexplained disorders of gonadal development.

Beginning on the 1st of October 2025
Contact: MC CHABOISSIER